Pledgeted versus nonpledgeted sutures in aortic valve replacement: Insights from a prospective multicenter trial

Objective The objective of this study was to compare short- and midterm clinical and echocardiographic outcomes according to the use of pledgeted sutures during aortic valve replacement. Methods Patients with aortic stenosis or regurgitation requiring aortic valve replacement were enrolled in a prospective cohort study to evaluate the safety of a new stented bioprosthesis. Outcomes were analyzed according to the use of pledgets (pledgeted group) or no pledgets (nonpledgeted group). The primary outcome was a composite of thromboembolism, endocarditis, and major paravalvular leak at 5 years of follow-up. Secondary outcomes included multiple clinical endpoints and hemodynamic outcomes. Propensity score matching was performed to adjust for prognostic factors, and subanalyses with small valve sizes (<23 mm) and suturing techniques were performed. Results The pledgeted group comprised 640 patients (59%), and the nonpledgeted group 442 (41%), with baseline discrepancies in demographic characteristics, comorbidities, and stenosis severity. There were no differences between groups in any outcome. After propensity score matching, the primary outcome occurred in 41 (11.7%) patients in the pledgeted and 36 (9.8%) in the nonpledgeted group (P = .51). The effective orifice area was smaller in the pledgeted group (P = .045), whereas no difference was observed for the mean or peak pressure gradient. Separate subanalyses with small valve sizes and suturing techniques did not show relevant differences. Conclusions In this large propensity score-matched cohort, comprehensive clinical outcomes were comparable between patients who underwent aortic valve replacement with pledgeted and nonpledgeted sutures up to 5 years of follow-up, but pledgets might lead to a slightly smaller effective orifice area in the long run.

Results: The pledgeted group comprised 640 patients (59%), and the nonpledgeted group 442 (41%), with baseline discrepancies in demographic characteristics, comorbidities, and stenosis severity. There were no differences between groups in any outcome. After propensity score matching, the primary outcome occurred in 41 (11.7%) patients in the pledgeted and 36 (9.8%) in the nonpledgeted group (P ¼ .51). The effective orifice area was smaller in the pledgeted group (P ¼ .045), whereas no difference was observed for the mean or peak pressure gradient. Separate subanalyses with small valve sizes and suturing techniques did not show relevant differences.
Conclusions: In this large propensity score-matched cohort, comprehensive clinical outcomes were comparable between patients who underwent aortic valve replacement with pledgeted and nonpledgeted sutures up to 5 years of followup, but pledgets might lead to a slightly smaller effective orifice area in the long run. ( Log rank P value = .51 Five-year outcomes according to the use of pledgets in the propensity score-matched cohort.

CENTRAL MESSAGE
Clinical outcomes were comparable for patients who underwent aortic valve replacement (AVR) with and without pledgets.

PERSPECTIVE
Whether to use pledgets for surgical AVR is an ongoing debate among surgeons. In a propensity score-matched analysis, comprehensive clinical outcomes were comparable between patients who underwent AVR with pledgeted and nonpledgeted sutures up to 5 years of follow-up. Nevertheless, pledgets might lead to a slight reduction of the EOA in the long run, but this finding requires external validation.
Aortic valve replacement (AVR) is the second-most commonly performed type of cardiac surgery, and rates are increasing because of an aging population. 1 Although AVR has been performed and improved over several decades, there is still debate among surgeons about the optimal implantation technique. An interesting topic that lacks consensus is whether to use pledgeted sutures to secure the prosthetic valve, because the literature shows conflicting results (Table 1). Some argue that the use of pledgeted sutures allow for more even distribution of mechanical forces and a tighter connection between the prosthesis and the aortic annulus/ root, thereby decreasing the incidence of paravalvular leak (PVL). 2 However, others believe that pledgets create an additional level of obstruction in the left ventricular outflow tract (LVOT), leading to a higher transvalvular gradient, a smaller effective orifice area (EOA), 4,5 and subsequently more frequent prosthesis-patient mismatch (PPM). 6 Theoretically, the use of pledgets could also induce higher rates of thromboembolism or endocarditis due to extra foreign material.
Within the PERIcardial SurGical AOrtic Valve Replace-meNt (PERIGON) Pivotal Trial of the Avalus bioprosthesis (Medtronic), the technical details for implantation were left to the discretion of the surgeon. We aimed to provide insight into the effect of pledgeted sutures during AVR on multiple clinical and hemodynamic outcomes. The primary outcome of interest was a composite of thromboembolism, endocarditis, and major PVL at 5-year follow-up.

Study Design
The PERIGON Pivotal Trial (www.clinicaltrials.gov, NCT02088554) is a prospective multicenter trial that is conducted at 38 sites across the United States, Canada, and Europe. In this single-armed trial, clinical and hemodynamic outcomes of the Avalus bioprosthesis (Medtronic), a stented bovine pericardial aortic valve, are evaluated. The study design was previously described in detail. 7,8 In short, symptomatic patients with moderate or severe aortic stenosis or chronic, severe aortic regurgitation who were admitted for surgical AVR according to clinical indication were enrolled. Patients with and without concomitant procedures, limited to coronary artery bypass grafting, left atrial appendage ligation, patent foramen ovale closure, ascending aortic aneurysm or dissection repair not requiring circulatory arrest, and subaortic membrane resection not requiring myectomy, were included. In the PERIGON Pivotal Trial protocol, surgical technical details were left to the surgeon's own consideration.
The trial was conducted according to the Declaration of Helsinki and good clinical practice. At each site, approval of the protocol was obtained from the institutional review board or ethics committee (Table E1), and written informed consent was provided by all patients. All deaths and valve-related adverse events were adjudicated by an independent clinical events committee, and study oversight was provided by an independent data and safety monitoring board (Baim Institute for Clinical Research). All echocardiographic data were evaluated by an independent core laboratory (MedStar).

Follow-up and End Points
Annual clinical and (transthoracic) echocardiographic evaluations were performed after the first year of follow-up. Patient and procedural characteristics, early outcomes (within 30 days postimplantation), and 5-year outcomes were compared among the pledgeted and nonpledgeted groups. The primary outcome was a composite of thromboembolism, endocarditis, and major PVL at 5-year follow-up. Other clinical parameters included in the early-and midterm outcome analysis consisted of mortality, thromboembolism, endocarditis, all and major hemorrhage, all and major PVL, explant, reintervention, and permanent pacemaker implantation.
Echocardiographic outcomes consisted of mean and peak pressure gradients calculated using the simplified Bernoulli formula, and EOA, which was determined using the continuity equation. EOA indexed (EOAi) by body surface area (BSA) was used to classify PPM. PPM was defined according to the Valve Academic Research Consortium 3 criteria as insignificant (EOAi >0.85 cm 2 /m 2 or >0.70 cm 2 /m 2 ), moderate (EOAi between 0.85 and 0.66 cm 2 /m 2 or 0.70 and 0.56 cm 2 /m 2 ), or severe (EOAi 0.65 cm 2 /m 2 or 0.55 cm 2 /m 2 ) for patients with a body mass index (BMI) <30 or !30, respectively. 9

Statistical Analysis
Continuous variables are presented as mean AE SD and categorical variables as number and percentage. The independent sample t test or Mann-Whitney U test was used to compare continuous variables, and c 2 or Fisher exact test was used for categorical variables. Early and 5-year clinical event rates (including 95% CI) were summarized using the Kaplan-Meier method, and the log rank test was used to calculate P values. An additional evaluation of hemodynamic performance postimplantation and at 5-year follow-up in valve sizes smaller than 23 mm was performed. Furthermore, hemodynamic performance according to suturing techniques within the nonpledgeted group were compared for the "mattress" (noneverted and everted mattress sutures) and "nonmattress" (continuous and simple interrupted sutures) groups to investigate differences not related to the use of pledgets.
Propensity score matching was performed to account for potential bias arising from the decision to use pledgets. Propensity scores were calculated on the basis of the following variables: age, male sex, BSA, Society of Thoracic  Data are presented as mean AE SD, median (interquartile range), or n (%) except where otherwise noted. SMD, Standardized mean difference; NYHA, New York Heart Association; STS, Society of Thoracic Surgeons; CVA, cerebrovascular accident; COPD, chronic obstructive pulmonary disease; CABG, coronary artery bypass grafting. *Includes implantable cardiac device, left atrial appendage closure, patent foramen ovale closure, resection of subaortic membrane not requiring myectomy, and dissection repair not requiring circulatory arrest. yThe annual diameter was determined intraoperatively and corresponds to the size of the replica end of the valve sizer.
Surgeons (STS) risk of mortality, New York Heart Association class III/IV, coronary artery disease, chronic obstructive pulmonary disease, hypertension, previous myocardial infarction, renal dysfunction/insufficiency, diabetes mellitus, atrial fibrillation, peripheral vascular disease, previous stroke/ cerebrovascular accident, left ventricular ejection fraction at baseline, mean pressure gradient at baseline, isolated/mixed aortic stenosis, and less invasive approach (hemisternotomy or right anterior thoracotomy). Baseline left ventricular ejection fraction and baseline mean pressure gradient were missing for 225 (20.8%) and 26 (2.4%) patients, respectively. To avoid losing patients in the postmatched analysis, the missing values were imputed with the median before entering propensity score matching. A 5-to-1 digits greedy 1:1 matching algorithm was used to form a propensity score-matched cohort for analysis. A 2-sided a level of 0.05 was used in all tests. The balance in baseline characteristics before and after propensity score matching was expressed in standardized mean differences. Statistical analyses were performed with SAS version 9.4 (SAS Institute Inc).
At 5 years of follow-up (Table 3), the composite outcome of thromboembolism, endocarditis, and major PVL occurred in 11.7% of the pledgeted group and in 9.8% of the nonpledgeted group (P ¼ .51  components were also comparable (Figures 1 and 2). The EOA was smaller in the pledgeted group (P ¼ .045), but no difference was observed for the mean or peak pressure gradient. The mean pressure gradient remained stable over time, whereas the EOA decreased especially in the pledgeted group ( Figure E2). The degree of PVL was consistent throughout follow-up ( Figure 3). The proportion of patients with any PPM at 5-year follow-up was similar between the groups (Table 3).

Subanalysis: Valve Sizes <23 mm
The baseline and procedural characteristics of patients with implanted valve sizes <23 mm are presented in Table  E5. Pledgets were used in 131 patients, and no pledgets in 112 patients. As observed in the entire cohort, differences among the groups existed in baseline age, STS risk of mortality, concomitant procedures, and implanted valve size. Additionally, the aortic crossclamp time was longer in the pledgeted group than in the nonpledgeted group   Table 4. The mean pressure gradient up to 30 days was lower in the pledgeted group compared with the nonpledgeted group (14.9 AE 4.6 vs 16.4 AE 5.6; P ¼ .027), but this difference was absent at 5-year follow-up. All other parameters were comparable at both follow-up points.

Subanalysis: Nonpledgeted Sutures
Stratification of patients within the nonpledgeted group resulted in 180 patients in the mattress subgroup and 205 in the nonmattress subgroup. Their baseline characteristics are summarized in Table E6. Differences were observed in BMI, New York Heart Association class III/IV, diabetes mellitus, hypertension, renal dysfunction/insufficiency, stroke/cerebrovascular accident, chronic obstructive pulmonary disease, coronary artery disease, left ventricular hypertrophy, and concomitant procedures. The hemodynamic performance up to 30 days and at 5-year follow-up is presented in Table  E7. At both time points, no differences related to suturing technique were found in echocardiographic variables, PPM, or PVL.

DISCUSSION
In a propensity score-matched analysis of a large international cohort, clinical outcomes at 30 days and 5 years of follow-up were comparable among patients who underwent surgical AVR with and without pledgeted sutures. Comparisons of pledgeted with nonpledgeted sutures in AVR in previous literature have mainly focused on hemodynamic performance (Table 1). Hence, insight into clinical outcomes is scarce. A potential disadvantage of pledgeted sutures is an increased risk of infection, pannus, or thrombus formation due to the presence of extra foreign material. A single study 6 evaluated thromboembolism rates, whereas endocarditis has never been studied to our knowledge. In our analysis, both adverse events rarely occurred within 30 days of follow-up and were comparable at 5 years. Thus, there was no evidence of higher rates of these events when pledgets were used.
PVL is another important variable in the choice whether to use pledgeted sutures. Several studies have investigated this parameter but have reported conflicting results. Englberger and colleagues 2 reported a reduction in PVL in the pledgeted sutures group. On the contrary, others reported no differences compared with nonpledgeted or  figure-of-eight sutures. [3][4][5][6] Our findings were in line with the latter studies.
Regarding other hemodynamic performance measures such as the EOA, previous results were ambiguous, too. Tabata and colleagues 4 observed a smaller EOA postimplantation in the pledgeted group that disappeared at 1 year, whereas Ugur and colleagues 5 described a larger EOA at that time point. In the current study, the EOA was equal between the groups at short-term follow-up; however, at 5 years a difference appeared as a result of a smaller EOA in the pledgeted group. This phenomenon might be due to subvalvular obstruction caused by the pledgets and tissue (pannus) formation/ingrowth developing over time, which could lead to elevated velocities in the LVOT. Theoretically, such obstruction would be more profound in a small LVOT because pledgets have a fixed size, but in our subanalysis of valve sizes <23 mm, the EOAs were similar between the pledgeted and nonpledgeted groups (Table 4). Another explanation could be related to measurement error because the smaller EOA was not reflected by the mean or peak pressure gradient. Measurement of the LVOT diameter is prone to error and has a drastic effect on the EOA value because this diameter is squared to obtain the LVOT area for the continuity equation. The presence of pledgets might complicate the echocardiographic measurement of the LVOT diameter even more when it is examined in close proximity to the aortic annulus. Because the absolute difference in EOA was<0.1 cm 2 , the difference was absent in small valve sizes, and other hemodynamic parameters were equal between the groups, the clinical relevance of this difference in EOA is questionable. External validation  Numerical data are presented as mean AE SD or median (interquartile range) according to their distribution, and categorical data are summarized as n (%). Data were compared using the independent samples t test, Mann-Whitney U test, and c 2 test/Fisher exact test, respectively.
of this finding and longer follow-up could provide valuable insights. A derivative of the indexed EOA is PPM. Because previous PERIGON substudies challenged the clinical relevance of this concept by outlining shortcomings regarding correspondence with elevated gradient and disproportional normalization by BSA, 10-12 we chose to mainly elaborate on primary echocardiographic parameters rather than PPM in this study. Although similar pressure gradients at 5 years were observed, a difference with lower values in the pledgeted group was found at 30 days, however, this dissimilarity was <1 mm Hg. Hence, it was not considered clinically important. To further investigate differences related to suturing technique, a subanalysis was executed within the nonpledgeted group. This analysis did not show any difference in the mattress and nonmattress suturing techniques.
Hemodynamic outcomes have received specific attention in smaller valve sizes. Two earlier studies reported similar hemodynamic parameters for pledgeted and nonpledgeted sutures. 4,5 Our results are in agreement with these findings.

Strengths and Limitations
A major advantage of the current study was that all 1082 patients received the same bioprosthetic valve, which eliminated any bias due to the type of prosthesis. Furthermore, the prospective design with independent adverse event adjudication and core laboratory assessment of echocardiograms enabled robust and consistent data-gathering up to 5 years of follow-up. Despite these strengths, there were limitations. Even though there was apparent harmony in patient characteristics after propensity score-matching, the study design could not guarantee complete comparability because adjustment was possible only for measured confounders. Specifically, we did not adjust for surgeon bias, and it is possible that surgeons who opted for one technique versus another might have different skills, leading to an inextricable confounding effect. The 1082 AVR procedures in this analysis were performed by 132 surgeons, some of whom solely used pledgeted (54 surgeons) or nonpledgeted sutures (33 surgeons). Hence, we did not incorporate surgeon data in the propensity score matching. To achieve complete comparability, randomized treatment allocation would have been a prerequisite, which was not the case. Furthermore, no correction methods were applied to the subanalyses, in which the statistical power was also decreased because of smaller sample sizes. Therefore, these results should be interpreted in the context of these limitations. An increased length of follow-up might have revealed more profound differences in outcomes. It would be of interest to observe whether the difference in EOA will persist and eventually lead to differences in clinical outcomes such as reintervention. Important aspects that remain unknown to the discussion of whether to use pledgeted sutures for surgical AVR are the feasibility of reoperations and future valvein-valve transcatheter AVR for degenerated bioprostheses. Unfortunately, no quantitative claims can be made on the basis of data from the current study. For future studies on this topic, these issues are highly relevant.

CONCLUSIONS
In a propensity score-matched analysis, comprehensive clinical outcomes were comparable between patients who underwent AVR with pledgeted and nonpledgeted sutures up to 5 years of follow-up ( Figure 4). Nevertheless, pledgets might lead to a slight reduction of the EOA in the long run, but this finding requires external validation.      1.1% (0.5%-2.7%) (n ¼ 5)